The research program outlined in this proposal is designed to elucidate the genetic basis for Wilms' tumor locus in band p13 of chromosome 11 was originally documented by cytogenetic analysis. Recently, we have isolated and begun the characterization of the gene (WT1) corresponding to this Wilms' tumor locus. The experimental program outlined in this proposal is designed to address the following major questions regarding the WT1 gene: What are the biochemical properties of the WT1 gene product? What are the normal functions of the WT1 gene product? How does inactivation of these functions lead to the occurrence of Wilms' tumor? What other gene products interact with WT1 in regulating cell proliferation? To answer these questions, we intend to proceed with the following approaches: 1. Analysis of the frequency and nature of mutation in the WT1 gene in Wilms' tumors;2. Development of antibody against the WT1 gene products and immunocytochemistry using these antibodies;3. Analysis of the interaction of the WT1 polypeptide with specific DNA sequences;4. Identification of genes transcriptionally controlled by the WT1 gene products; 5. Identification, isolation and characterization of other genes which cooperate with the WT1 gene products 7. Identification of polypeptides which show high affinity for the WT1 gene products; 8. Development and analysis of mouse models for WAGR deletions and Wilms' tumor.